Watchman Afib Device Gets Second Chance

The Watchman transcatheter left atrial appendage closure device will be considered again by an FDA advisory committee for the prevention of stroke or systemic embolism in patients with nonvalvular atrial fibrillation.

On Wednesday, the agency's Circulatory System Devices Panel will mull whether new data accumulated since the FDA declined to approve the device more than 3-and-a-half years ago provides support for approval at this point.

"The advisory panel will be asked to assess whether these data demonstrate a reasonable assurance of safety and effectiveness and address the benefit-risk profile of the Watchman device for the prevention of stroke and systemic embolism in these patients," according to review documents released by the FDA ahead of the meeting.

The first major trial to evaluate the Watchman device -- which is made by Boston Scientific (after acquiring Atritech) -- was the PROTECT AF trial, with 2-year results establishing noninferiority of the device versus warfarin on a composite of stroke, cardiovascular death, and systemic embolism. That was accompanied, however, by an increased risk of bleeding and procedure-related complications with the Watchman.

Those results were enough to convince an FDA advisory committee to recommend approval of the device in 2009 in a relatively split vote of 7-5. The five panelists voting against recommending approval balked at the greater safety risks with the device.

In March 2010, however, the FDA went against that decision and declined to approve the Watchman, citing safety concerns and other issues with the conduct of the trial.

"Although FDA recognized that the PROTECT AF trial showed potential clinical benefit of the Watchman device, the agency concluded that the study results did not demonstrate a reasonable assurance of device safety and effectiveness," the review documents stated.

The FDA worked with the company to design a new trial -- called PREVAIL -- to address some of the problems with PROTECT AF. The new trial included higher-risk patients, excluded those on chronic clopidogrel therapy, aimed for improved anticoagulation with warfarin, and required at least 25% of patients to be enrolled by new operators and at least 20% to be enrolled at new investigation sites.

The PREVAIL results -- released earlier this year -- showed that the trial met the primary safety endpoint, with a 2.2% rate of death, ischemic stroke, systemic embolism, or complications requiring intervention related to the procedure or device. The rate of vascular complications overall was 4.4%, about half that seen in PROTECT AF (8.7%).

But one of the two coprimary efficacy endpoints in PREVAIL was met. Non-inferiority between the Watchman and warfarin was established for the composite of ischemic stroke or systemic embolism, but not for the composite of stroke, systemic embolism, or cardiovascular or unexplained death.

In order to recommend approval, the FDA panel will have to consider the entirety of the evidence, including the initial PROTECT AF results, data from a continued access registry that followed PROTECT AF, the PREVAIL results, and longer-term results from PROTECT AF that were reported earlier this year. At about 4 years of follow-up, the rate of stroke, cardiovascular death, or systemic embolism significantly favored the Watchman over warfarin, the first time a significant difference was observed between the two treatments.

The panel will also discuss Boston Scientific's proposed indication for the device: "The Watchman left atrial appendage closure therapy is intended to prevent embolism of thrombus from the left atrial appendage and thus reduce the risk of stroke, systemic embolism, and cardiovascular death in high-risk patients with nonvalvular atrial fibrillation who are eligible for warfarin therapy, but for whom the risks posed by long-term warfarin therapy outweigh the benefits."

This indication was compelling when warfarin was the only anticoagulation agent available, but in the years that Watchman has been in development three newer oral anticoagulants, the so-called NOACs, have come to market: dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis), a sea change that may make warfarin tolerance a moot point.

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